Homozygous LOXL2 variant in individuals affected by non-syndromic occipital encephalocele

Background: Occipital encephaloceles is a rare congenital defect in which meninges and the brain protrude out as a sac-like structure through opening in the skull. The condition can result in neurologic complications as well as structural abnormalities of the skull. To the best of our knowledge, no genetic variant has been identified as an underlying cause of non-syndromic occipital encephaloceles.

Methods: In this study, I report a family with 2 individuals having large occipital encephalocele. Clinical and radiological examination did not reveal any other neurological or skeletal manifestations in both affected individuals.

Results: Exome sequencing detected the previously unreported homozygous single nucleotide duplication (NM_002318.3:c.64dupC) in LOXL2 gene. This is a nonsense variant (NP_002309.1:p.Leu22Profs*7) leading to a premature truncation and loss-of-function of the lysyl oxidase-like 2 protein. The variant is segregating in an autosomal recessive manner in a family. Both parents are heterozygous carriers for the variant while unaffected sibs have wild type sequence.

Conclusion: We hypothesize that LOXL2 is a potential candidate gene for occipital encephalocele due to the established role of LOXL3, a close paralog of LOXL2, in craniofacial development. This case illustrates the power of exome sequencing to establish genetic diagnosis and expands the spectrum of genetic defects in occipital encephalocele and related disorders.